Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome

Abstract

Background: Werner syndrome is a progeroid disorder characterized by premature age-related phenotypes. Although it is well established that autosomal recessive mutations in the WRN gene is responsible for Werner syndrome, the molecular alterations that lead to disease phenotype remain still unidentified.

Results: To address whether epigenetic changes can be associated with Werner syndrome phenotype, we analysed genome-wide DNA methylation profile using the Infinium MethylationEPIC BeadChip in the whole blood from three patients affected by Werner syndrome compared with three age- and sex-matched healthy controls. Hypermethylated probes were enriched in glycosphingolipid biosynthesis, FoxO signalling and insulin signalling pathways, while hypomethylated probes were enriched in PI3K-Akt signalling and focal adhesion pathways. Twenty-two out of 47 of the differentially methylated genes belonging to the enriched pathways resulted differentially expressed in a publicly available dataset on Werner syndrome fibroblasts. Interestingly, differentially methylated regions identified CERS1 and CERS3, two members of the ceramide synthase family. Moreover, we found differentially methylated probes within ITGA9 and ADAM12 genes, whose methylation is altered in systemic sclerosis, and within the PRDM8 gene, whose methylation is affected in dyskeratosis congenita and Down syndrome.

Conclusions: DNA methylation changes in the peripheral blood from Werner syndrome patients provide new insight in the pathogenesis of the disease, highlighting in some cases a functional correlation of gene expression and methylation status.

Keywords: DNA methylation; Systemic sclerosis; Werner syndrome.

Fig. 1

SSc typical skin signs in WS patients. a Skin unable to be lifted in pliers and/or pinched. b Cutaneous ulcer with calcinosis. c Capillaroscopic alterations and ectasias

Fig. 2

DNA methylation alterations in Werner syndrome. a Volcano plot of DMPs between WS patients and CTRs. The difference between mean DNA methylation values in WS patients and in CTRs is plotted on the x-axis, while the non-adjusted P value for ANOVA between the two groups is on the y-axis (− 1 × log10 scale). The green line corresponds to a non-adjusted P value of 0.001. b DNA methylation profile of the CpG island located in the CERS3 gene

Fig. 3

Differential expression of CERS1, CERS3, ITGA9 and ADAM12 genes based on the publicly available dataset on WS fibroblast analyses